Approach to refractory gastroesophageal reflux symptoms in adults

INTRODUCTION — 

Despite optimal treatment with proton pump inhibitors (PPIs), some individuals with gastroesophageal reflux disease (GERD) continue to have reflux symptoms and/or objective evidence of GERD, such as erosive esophagitis or abnormal esophageal acid exposure. This topic reviews an approach to patients with refractory GERD. The clinical manifestations, diagnosis, and initial management of GERD and the diagnosis and management of patients with non-acid reflux are discussed separately.

●(See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults".)

●(See "Initial management of gastroesophageal reflux disease in adults".)

●(See "Non-acid reflux: Clinical manifestations, diagnosis, and management".)

TERMINOLOGY

●Refractory gastroesophageal reflux disease (GERD) – Refractory GERD is defined as persistent symptoms and objective evidence of GERD despite optimal medical therapy in patients with prior objective evidence of GERD [1]. Objective evidence of GERD includes erosive esophagitis, peptic stricture, Barrett's esophagus, or abnormal esophageal acid exposure on reflux monitoring performed off therapy.

●Refractory GERD symptoms – Refractory GERD symptoms, part of the definition of refractory GERD, refer to persistent symptoms of heartburn or regurgitation on optimal medical therapy in patients with prior objective evidence of GERD (erosive esophagitis, peptic stricture, Barrett's esophagus, or abnormal esophageal acid exposure on reflux monitoring performed off therapy) [2]. Although some of these patients have incomplete control of their GERD, others have symptoms caused by non-GERD etiologies that coexist with GERD. These etiologies include functional heartburn, reflux hypersensitivity, esophageal mucosal disorders, gastric motor disorders, supragastric belching, rumination syndrome, or vomiting syndromes. These diagnoses can mimic GERD and/or coexist with it. (See 'Causes of refractory GERD symptoms' below.)

●Refractory reflux-like symptoms – Refractory reflux-like symptoms refer to persistent symptoms of heartburn or regurgitation on optimal medical therapy in patients without prior objective evidence of GERD. Refractory reflux-like symptoms can be caused by GERD or non-GERD etiologies.

●Optimal acid suppressive therapy – Optimal acid suppressive therapy consists of a stable dose of a twice-daily proton pump inhibitor (PPI) or a once-daily, maximum dose of potassium-competitive acid blocker (PCAB) for at least eight weeks.

EPIDEMIOLOGY — 

Approximately one-third of patients with reflux-like symptoms (ie, heartburn or regurgitation) have GERD with erosive esophagitis on upper endoscopy, and one-third have GERD with nonerosive reflux (NERD), or reflux-like symptoms with a normal endoscopy and abnormal results on pH testing or manometry [3]. The remaining one-third have diagnoses other than GERD, commonly functional heartburn or reflux hypersensitivity.

Up to 50 percent of patients with reflux-like symptoms experience inadequate symptom relief with proton pump inhibitors (PPIs) [4-6]. In a population-based survey of United States participants, 54 percent of those with gastrointestinal symptoms had persistent symptoms despite daily PPI use [6].

Among those with documented GERD, those with erosive esophagitis are more likely to respond to PPI therapy, compared with patients with NERD. Response rates to a once-daily PPI at four weeks are approximately 56 percent in patients with erosive esophagitis and only approximately 37 percent in patients with NERD [7,8]. Consequently, most individuals with refractory GERD symptoms have nonerosive reflux disease.

CAUSES OF REFRACTORY GERD SYMPTOMS — 

Causes of persistent symptoms in individuals with GERD include persistent gastroesophageal reflux, coexisting disorders of gut-brain interaction, anatomic or motor disorders of the upper gastrointestinal tract, and other diagnoses.

Persistent reflux — Persistent gastroesophageal reflux can be due to poor adherence or response to acid suppressive therapy or ongoing reflux.

●Poor adherence to proton pump inhibitor (PPI) therapy – Poor adherence to the timing (ie, 30 to 45 minutes before a meal) or daily dosing of PPI therapy frequently causes inadequate acid suppression and refractory GERD symptoms [9-12]. Adherence to daily PPI dosing is relatively poor, with almost 50 percent of patients becoming on-demand users within four weeks after initiating treatment [13]. In a study that included 1,959 adults with GERD, only 47 percent of participants who received PPI therapy from their primary care physician and 39 percent of those using over-the-counter PPIs took them correctly [14]. (See "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders", section on 'Dose and timing of administration'.)

●Rapid metabolism of PPIs – PPIs are metabolized through the hepatic cytochrome P450 system, with CYP2C19 having the dominant role. Genetic polymorphisms of CYP2C19 affect its activity and, in turn, the metabolism of PPIs and their level of gastric acid suppression. Individuals who carry one or two CYP2C19 alleles with increased function are referred to as "rapid" or "ultrarapid" metabolizers, respectively [15]. These patients can experience diminished suppression of gastric acid with PPIs and higher rates of PPI failure. Approximately 14 percent of American and 32 percent of European populations have CYP2C19 "rapid" or "ultrarapid" metabolizer phenotypes [16]. (See "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders", section on 'Pharmacology'.)

●Residual acid reflux – Residual acid reflux is a relatively common cause of refractory GERD symptoms in patients on once-daily PPI therapy; however, it occurs uncommonly in those on twice-daily PPIs [17-21]. In one retrospective review of 135 adults with refractory GERD symptoms who underwent pH monitoring, pH testing results were abnormal in 31 and 4 percent of those taking a PPI once or twice daily, respectively [22].

In some individuals, highly acidic gastric juice develops postprandially at the gastroesophageal junction. This is termed the acid pocket. Although the presence of an acid pocket could potentially cause re-reflux of gastric acid, limited evidence suggests that this does not play a significant role in refractory GERD. In a study of 18 patients with GERD, neither the position nor pH of the acid pocket correlated with participantsꞌ response to PPI therapy [23]. (See "Pathophysiology of gastroesophageal reflux disease", section on 'Impaired esophageal acid clearance'.)

●Weakly acidic reflux – Weakly acidic reflux events may contribute to refractory symptoms in those with GERD. Weakly acidic reflux is reflux that decreases esophageal pH to between four and seven. It typically occurs postprandially and consists of the reflux of gastric contents whose pH has been neutralized by food and swallowed saliva [24].

Weakly acidic reflux is uncommon in healthy persons and those with GERD who are not taking acid suppressive medications (PPIs and potassium-competitive acid blockers [PCABs]). It is responsible for approximately 15 percent of symptomatic reflux episodes in those off PPI therapy. By contrast, treatment with potent acid suppressive medications increases weakly acidic reflux events in both healthy individuals and those with GERD.

In persons with refractory GERD symptoms, an abnormal number of weakly acidic reflux events supports the existence of ongoing gastroesophageal reflux. In patients with symptomatic GERD on double-dose PPI therapy, having over 80 total reflux episodes per day is adjunctive evidence for continuous, objective GERD. In patients with refractory GERD symptoms, 30 to 40 percent of weakly acidic reflux events correlate with symptoms, most commonly symptoms of regurgitation and cough [24-26].

The clinical manifestations, diagnosis, and management of weakly acidic and non-acid reflux are discussed separately. (See "Non-acid reflux: Clinical manifestations, diagnosis, and management", section on 'Pathogenesis' and "Pathophysiology of gastroesophageal reflux disease", section on 'Mechanisms of gastroesophageal reflux disease'.)

●Bile reflux – Bile reflux may contribute to persistent symptoms in some individuals with refractory GERD. Bile reflux is distinct from weakly acidic reflux and occurs primarily in an acidic environment. In a study of 65 individuals with refractory reflux-like symptoms, 11 percent had only abnormal acid exposure, 38 percent had only abnormal bile exposure, and 26 percent had abnormal exposure of both acid and bile [27]. Furthermore, in a carefully selected group of patients with refractory reflux-like symptoms, baclofen significantly reduced both bile reflux exposure and heartburn. Although these studies suggest a potential role for assessing bile reflux in patients with refractory GERD symptoms, bile reflux monitoring is currently not available. (See "Pathophysiology of gastroesophageal reflux disease" and "Non-acid reflux: Clinical manifestations, diagnosis, and management".)

Overlap with disorders of gut-brain interaction — Many individuals with refractory GERD have coexisting functional gastrointestinal disorders, which are broadly categorized as disorders of gut-brain interaction. The functional esophageal disorders that most commonly overlap with GERD include functional heartburn and reflux hypersensitivity [28,29].

The main underlying mechanism of functional esophageal disorders is esophageal hypersensitivity. It is analogous to the visceral hyperalgesia that characterizes other disorders of gut-brain interaction, such as irritable bowel syndrome and functional dyspepsia. Proposed mechanisms of esophageal hypersensitivity include central and peripheral hyperalgesia, altered central processing of visceral stimuli, altered autonomic activity, and psychosocial factors, such as stress/anxiety, hypervigilance, and sleep deprivation. (See "Functional dyspepsia in adults" and "Clinical manifestations and diagnosis of irritable bowel syndrome in adults".)

●Reflux hypersensitivity – Reflux hypersensitivity is a common cause of refractory GERD symptoms. An estimated 13 to 36 percent of patients with refractory GERD symptoms demonstrate an overlap with reflux hypersensitivity.

Reflux hypersensitivity is characterized by retrosternal symptoms, including heartburn and chest pain, that are associated with nonpathologic esophageal acid exposure. According to Rome IV criteria, a diagnosis of reflux hypersensitivity requires a symptom onset at least six months prior to the diagnosis with all of the following occurring within the last three months [30]:

•Retrosternal symptoms that include heartburn or chest pain

•Normal endoscopy without evidence of eosinophilic esophagitis

•Absence of major esophageal motor disorders (eg, achalasia/esophagogastric junction outflow obstruction, diffuse esophageal spasm, hypercontractile esophagus, absent peristalsis)

•Evidence that reflux events trigger symptoms despite normal acid exposure on pH monitoring (a response to antisecretory therapy does not preclude the diagnosis)

●Functional heartburn – Functional heartburn is a common cause of refractory GERD symptoms. Up to 63 percent of patients with persistent heartburn while on a PPI have an overlap with functional heartburn [28,29].

According to Rome IV criteria, a diagnosis of functional heartburn requires a symptom onset at least six months prior to the diagnosis with all of the following occurring within the last three months [30]:

•Burning retrosternal discomfort or pain

•Absence of symptom relief despite optimal antisecretory therapy

•Absence of evidence that gastroesophageal reflux (abnormal acid exposure and symptom reflux association) or eosinophilic esophagitis are the cause of symptoms

•Absence of major esophageal motor disorders (eg, achalasia/esophagogastric junction outflow obstruction, diffuse esophageal spasm, hypercontractile esophagus, absent peristalsis)

Most patients with functional heartburn have chronic symptoms that vary in severity over time. In one study of 40 individuals with functional heartburn, 66 percent remained symptomatic almost two years after initial diagnosis [31].

As with the other functional esophageal disorders, the main underlying mechanism responsible for symptoms in functional heartburn is esophageal hypersensitivity. Individuals with functional heartburn demonstrate increased esophageal sensitivity to chemical, mechanical, and electrical stimuli [32-35].

●Functional dyspepsia – An overlap of GERD with functional dyspepsia may also lead to refractory GERD symptoms [36]. Functional dyspepsia and GERD commonly coexist, with one meta-analysis reporting that 41 percent of individuals with GERD also had symptoms of functional dyspepsia [37] (see "Functional dyspepsia in adults", section on 'Selected comorbidities'). Functional dyspepsia is discussed separately. (See "Functional dyspepsia in adults".)

●Esophageal hypervigilance – Esophageal hypervigilance comprises cognitive and affective processes that amplify esophageal symptoms. These include specific attention to esophageal sensations, increased anxiety about symptoms and expected pain, and catastrophic thoughts about symptom consequences [38,39]. In a cohort of adults with reflux symptoms, esophageal hypervigilance was associated with symptom severity but not correlated with acid burden or symptom index [40].

●Psychologic comorbidities – In population-based studies, anxiety and depression are associated with increased GERD-related symptoms [41]. Patients whose reflux-like symptoms correlate poorly with acid reflux events display higher levels of anxiety than those whose symptoms do correlate [42]. Psychologic comorbidities are also common in individuals with functional heartburn [43]. Anxiety, depression, and somatization can affect patientsꞌ response to antireflux treatment [38].

●Other disorders of gut-brain interaction – Other disorders that can coexist with GERD and cause refractory symptoms include supragastric belching and rumination syndrome. These are discussed separately. (See "Rumination syndrome" and "Overview of intestinal gas and bloating", section on 'Belching'.)

Anatomic or motor abnormalities of the upper gut — Motor and anatomic esophageal disorders can cause ongoing symptoms in those with GERD. They include gastric motor abnormalities such as gastroparesis and esophageal motor abnormalities such as achalasia, ineffective esophageal motility, and absent contractility. Anatomic abnormalities include esophageal stricture or cancer as well as conditions that may also lead to esophageal functional abnormalities, including a large hiatal hernia, post sleeve gastrectomy, and post peroral esophageal myotomy (POEM).

Esophageal mucosal disorders — Esophageal mucosal disorders may overlap with GERD and cause refractory GERD symptoms. These include eosinophilic, lymphocytic, infectious, and pill-induced esophagitis.

Alternative diagnoses — An overlap with other esophageal and nonesophageal diseases that can mimic GERD may result in refractory GERD symptoms. These include cardiopulmonary disorders, laryngeal disorders, and vomiting syndromes. (See 'Evaluation of patients with persistent symptoms' below.)

INITIAL ASSESSMENT — 

The initial assessment of individuals with refractory GERD consists of a careful history and focused physical examination to assess the timing, quality, and severity of reflux-like symptoms; medication adherence; degree of symptom response to acid suppressive medications; and specific alarm features that increase the risk of severe disease, such as esophageal and gastric cancer.

Alarm features — The initial assessment should evaluate for alarm features that may be suggestive of a gastrointestinal malignancy. These include:

●Evidence of gastrointestinal bleeding (hematemesis, melena, hematochezia, occult blood in stool, iron deficiency anemia)

●Anorexia

●Unexplained weight loss

●Dysphagia

●Odynophagia

●Persistent vomiting

Other symptoms and signs — Patients with refractory GERD symptoms require careful evaluation of their type of symptoms, symptom timing in relation to medication, and symptom severity and progression over time. This includes the degree to which the patientꞌs symptoms impair functioning and quality of life. Clinicians should also ask about foods and behaviors that trigger symptoms and patient adherence to lifestyle modifications that may reduce symptoms (table 1 and table 2). (See 'Reinforce lifestyle and dietary modifications' below and "Initial management of gastroesophageal reflux disease in adults", section on 'Lifestyle and dietary modification'.)

The history should differentiate symptoms of heartburn from epigastric burning or pain, the latter of which can indicate dyspepsia, peptic ulcer disease, biliary colic, or, less commonly, pancreatic or gastroduodenal malignancy. Individuals with severe or rapidly worsening symptoms should undergo prompt diagnostic workup, particularly if they have alarm features (see 'Patients with alarm features' below). Predominant atypical GERD symptoms, such as cough or chest pain, should prompt consideration of cardiopulmonary etiologies (see "Clinical manifestations and diagnosis of gastroesophageal reflux in adults", section on 'Patients without classic symptoms'). We also ask about symptoms of depression and anxiety, as these disorders can decrease the response to GERD treatment.

The physical examination should assess for weight loss and signs of anemia or occult gastrointestinal blood loss.

Adherence and response to acid suppression medications

●Medication adherence – Because proton pump inhibitor (PPI) adherence is often poor, and suboptimal adherence can decrease medication efficacy, we ask all patients how often they take acid suppressive medications (ie, daily versus as needed) and how they time their medication in relation to meals. (See 'Optimize acid suppressive therapy' below.)

●Response to medications – Evaluation of a patientꞌs response to acid suppression medications includes the degree to which their symptoms improve with medication, whether symptom control wanes towards the end of the dosing cycle, and the time course of symptom response. Most individuals with GERD experience symptom relief within five to seven days and complete endoscopic healing within eight weeks after initiating drug therapy. However, the time to symptom resolution after starting acid suppression therapy varies, with approximately 12 percent of patients per week experiencing complete relief of heartburn after initiating PPI therapy [44].

Healing may take longer in some patients with severe erosive esophagitis (eg, Los Angeles grade C or D esophagitis), and esophageal healing may precede symptom resolution. In patients with erosive esophagitis, the discrepancy between healing and symptom resolution at the conclusion of PPI therapy is approximately 15 percent [45].

INITIAL MANAGEMENT — 

The timing and extent of diagnostic evaluation in adults with refractory GERD symptoms depend on the patientꞌs specific symptoms and the presence of alarm features. A suggested approach to the evaluation and management of patients with refractory GERD appears in the algorithm (algorithm 1).

Patients with alarm features

●Evaluation – In individuals with new alarm features, we perform an early upper endoscopy (within one to two weeks) with esophageal biopsies to determine the underlying etiology (see 'Alarm features' above). Upper endoscopy should not be delayed pending a trial of empiric antireflux therapy. In patients who have previously undergone an upper endoscopy, we repeat the endoscopy if new alarm features have developed since the prior one.

Upper endoscopy can identify a large hiatal hernia, esophageal narrowing or stricture, or esophageal dilation suggestive of achalasia (see "Achalasia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Upper endoscopy' and "Hiatus hernia", section on 'Upper endoscopy'). Endoscopy can also identify esophageal mucosal disorders, such as infectious, pill-induced, or eosinophilic esophagitis. Ruling out eosinophilic esophagitis requires adequate biopsies (two to four biopsies of the distal esophagus and two to four from the mid or proximal esophagus). (See "Clinical manifestations and diagnosis of eosinophilic esophagitis (EoE)", section on 'Histology'.)

Individuals with alarm features in whom upper endoscopy is unrevealing may require additional evaluation depending on the type and severity of their symptoms. This might include abdominal imaging in patients with concurrent weight loss, esophageal manometry in those with dysphagia, or colonoscopy in those with suspected lower gastrointestinal blood loss.

●Management – We manage patients with alarm features and a negative diagnostic workup similarly to those without alarm features. (See 'Patients without alarm features' below.)

Patients with signs of persistent GERD or GERD-related complications should be managed with optimized acid suppressive therapy and other measures used in those with severe residual acid reflux. (See 'Optimize acid suppressive therapy' below and 'Residual erosive esophagitis or acid reflux' below.)

Patients without alarm features

Reinforce lifestyle and dietary modifications — In individuals without alarm features, we start by reinforcing lifestyle and dietary modifications [46]. These include avoiding identified dietary triggers, modifying the timing and quantity of food intake, losing weight for those who are overweight or have had recent weight gain, addressing psychosocial stressors that trigger symptoms, and minimizing medications that can cause or exacerbate GERD (table 1). We work with patients to develop an individualized plan that targets specific lifestyle changes and reinforce this plan periodically (table 2). Lifestyle changes for managing GERD are discussed separately. (See "Initial management of gastroesophageal reflux disease in adults", section on 'Lifestyle and dietary modification'.)

We also counsel all individuals regarding the pathophysiology of acid reflux. This includes discussing the role of the gut-brain axis in modulating GERD symptoms. (See "Initial management of gastroesophageal reflux disease in adults", section on 'Education and counseling'.)

Individuals with GERD whose initial assessment suggests psychologic comorbidity or esophageal hypervigilance should receive counseling regarding how psychologic conditions can augment GERD symptoms, diagnosis and treatment of specific mental health disorders, and referral to a behavioral health specialist if their symptoms persist [47].

Optimize acid suppressive therapy

●Initial steps for all patients – Acid suppressive therapy includes treatment with either a proton pump inhibitor (PPI) or a potassium-competitive acid blocker (PCAB), most commonly vonoprazan. We encourage all individuals with refractory GERD who are on acid suppressive therapy with a PPI or PCAB to take these medications daily rather than on an as-needed basis. (See 'Persistent reflux' above.)

Patients with a partial response to acid suppressive therapy can try adding a second agent as needed for intermittent symptoms, such as an antacid, alginate-based medications (eg, aluminum hydroxide-magnesium carbonate or Gaviscon), or a histamine 2 receptor antagonist. (See 'Residual erosive esophagitis or acid reflux' below.)

●Patients taking PPIs – In patients with refractory GERD symptoms despite taking PPI therapy once daily, we optimize dose timing and/or try splitting the PPI dose or switching to a different PPI prior to doubling the PPI dose.

•Optimize dose timing – In patients with refractory GERD symptoms on PPI therapy, we emphasize the importance of medication timing. PPIs should be administered 30 to 60 minutes before a meal for maximal inhibition of the proton pumps. Administration of PPIs before a meal provides better control of intragastric pH compared with administration during or after a meal [48].

Adherence to the timing of PPI dosing can improve refractory reflux-like symptoms. For example, in a trial of 64 adults with persistent heartburn and suboptimal PPI dosing time, randomization to optimal PPI dosing time (30 to 60 minutes before a meal once daily) improved symptom severity and frequency score compared with a control group randomized to continue suboptimal PPI dosing time [49].

•Split PPI dose – For those with daytime and nocturnal symptoms who are taking a standard dose PPI in the morning, splitting the dose into morning and evening doses may improve symptoms (eg, change lansoprazole 30 mg daily to 15 mg twice daily, 30 to 60 minutes before meals). Physiologic studies show improved control of nocturnal acid breakthrough with split PPI dosing compared with once-daily dosing [50].

•Switch to a different PPI – When a patientꞌs symptoms persist despite optimizing the acid suppressive medication, we suggest switching to a different PPI (eg, lansoprazole 30 mg daily to rabeprazole 20 mg daily). Although switching from a PPI to a PCAB is a reasonable alternative, we typically try switching the PPI first because approximately 15 percent of patients with refractory GERD symptoms will experience symptomatic improvement by switching to a different PPI [51].

•Double the PPI dose – When the aforementioned measures do not improve the patientꞌs symptoms, we double the PPI dose to twice daily for eight weeks (eg, lansoprazole 30 mg twice daily). In one study of individuals with persistent GERD symptoms on once-daily PPI therapy, doubling the PPI dose increased overall symptom improvement by 22 to 26 percent [52,53].

In patients on once-daily PPI therapy, switching and doubling the PPI dose appear to have comparable efficacy [52]. In a trial of 328 participants with persistent GERD symptoms while taking single-dose lansoprazole, the percentage of heartburn-free days was similar between those randomized to esomeprazole 40 mg once daily, compared with lansoprazole 30 mg twice daily [51].

Some experts have suggested providing a double-dose PPI with four daily doses (eg, lansoprazole 15 mg four times daily). However, this strategy is difficult for patients, and supporting evidence for this approach is limited to a physiologic study that demonstrated a greater reduction in intragastric pH over 24 hours with PPI dosing four times daily, compared with once or twice daily dosing [54].

Data to support additional symptom improvement with a PPI dose escalation above double dosing are lacking.

●Patients taking PCABs – The optimal approach in individuals with refractory GERD symptoms who are taking a PCAB is less well defined. Some patients with GERD receive a PCAB as part of initial management, especially patients with Los Angeles grade C or D erosive esophagitis (see "Initial management of gastroesophageal reflux disease in adults", section on 'Patients with esophagitis' and "Initial management of gastroesophageal reflux disease in adults", section on 'Vonoprazan as alternative'). When these patients have refractory GERD symptoms, we increase the dose of vonoprazan to 20 mg once daily if the patient is taking only 10 mg daily.

●Patients with predominant regurgitation symptoms – In patients with regurgitation as the predominant symptom, it is reasonable to add baclofen. (See 'Residual erosive esophagitis or acid reflux' below.)

EVALUATION OF PATIENTS WITH PERSISTENT SYMPTOMS — 

In individuals with persistent symptoms despite lifestyle changes and optimizing acid suppressive therapy, we tailor additional diagnostic workup to the patient's prior testing and predominant symptoms.

No recent prior endoscopy — We perform an upper endoscopy with esophageal biopsies if needed in all individuals whose symptoms persist despite optimized acid suppression if they have not had one in the past six months.

Normal upper endoscopy — Individuals with refractory GERD symptoms despite therapy with a potassium-competitive acid blocker (PCAB) or twice-daily proton pump inhibitor (PPI) who have an unrevealing upper endoscopy should undergo esophageal impedance pH testing on PPI or PCAB treatment and esophageal manometry.

Esophageal impedance pH testing — We prefer esophageal impedance pH testing to wireless pH capsule or traditional pH probe because impedance pH testing can detect weakly acidic and alkaline reflux and correlate different types of reflux events with patient symptoms [55,56]. Esophageal pH monitoring with impedance testing should take place on treatment (ie, PCAB or twice-daily PPI) to determine reflux burden and assess for the presence of continued pathologic acid or non-acid exposure while on therapy [57]. (See "Esophageal multichannel intraluminal impedance testing", section on 'Testing on or off proton pump inhibitors'.)

In persons with normal esophageal acid exposure, esophageal impedance pH testing can differentiate between reflux hypersensitivity and functional heartburn by correlating symptoms with reflux events by using symptom index and symptom association probability [58]. Patients whose symptoms correlate with reflux events on esophageal impedance pH testing have reflux hypersensitivity. Those without symptom correlation typically have functional heartburn. Impedance testing can also diagnose supragastric belching by identifying spikes of increased impedance in the esophagus that migrates proximally. The performance and interpretation of esophageal impedance pH testing are reviewed separately. (See "Esophageal multichannel intraluminal impedance testing".)

Esophageal manometry — We perform esophageal manometry in all individuals with refractory GERD and no mucosal abnormality on endoscopy to exclude an esophageal motor disorder [57,59,60]. An alternative approach reserves esophageal manometry for patients with symptoms that suggest a motility disorder (eg, dysphagia or chest pain) or those with normal results on esophageal impedance pH testing. Esophageal manometry can differentiate GERD from rumination syndrome by detecting gastric straining preceding or during reflux events that extend to the proximal esophagus. Esophageal manometry is discussed separately. (See "Overview of gastrointestinal motility testing", section on 'Esophageal manometry'.)

MANAGEMENT BASED ON TEST RESULTS — 

Subsequent management is based on the results of the esophageal pH impedance testing, upper endoscopy, and esophageal manometry. Upper endoscopy may reveal residual erosive esophagitis. Esophageal pH impedance testing can reveal residual acid reflux (ie, GERD), reflux hypersensitivity, functional heartburn, or other esophageal or nonesophageal disorders.

Residual erosive esophagitis or acid reflux — Treatment options in individuals with evidence of residual erosive esophagitis on endoscopy or acid reflux on esophageal impedance pH testing include medical, surgical, or endoscopic interventions. Selection between different treatment options depends on the severity of the patientꞌs symptoms, type of symptoms (eg, predominant regurgitation), presence of ongoing esophageal mucosal damage, and patient preference.

●Intermittent symptoms – We initiate histamine 2 receptor antagonists (H2RAs) or sodium alginate, if available, in patients who have intermittent or nocturnal breakthrough symptoms.

•H2RAs – In patients with predominantly nocturnal symptoms, we suggest adding an H2RA at bedtime [61]. H2RAs are best used intermittently because tachyphylaxis develops rapidly and can occur after only one week of therapy [62-66]. (See "Initial management of gastroesophageal reflux disease in adults", section on 'Mild, intermittent symptoms'.)

•Alginates – Adding an antacid that contains sodium alginate (eg, aluminum hydroxide-magnesium carbonate or Gaviscon) is an option for patients with refractory GERD who demonstrate abnormal esophageal acid exposure on esophageal impedance pH testing while on a twice-daily PPI. Alginates form a viscous raft over the acid pocket in the proximal stomach. Although sodium alginate is used for the initial management of reflux-like symptoms, its efficacy in refractory GERD has not been demonstrated. (See "Pathophysiology of gastroesophageal reflux disease", section on 'Impaired esophageal emptying'.)

●Severe GERD – In individuals with residual erosive esophagitis on treatment or those with severe symptoms and evidence of objective GERD, therapeutic options include using a potassium competitive acid blocker (PCAB), antireflux surgery, or endoscopic procedures.

•Potassium competitive acid blockers (PCABs) – In patients with refractory GERD and continued erosive esophagitis on repeat endoscopy while on treatment, we switch to a PCAB, such as vonoprazan 20 mg once daily. Compared with proton pump inhibitor (PPIs), PCABs demonstrate higher rates of initial healing and maintenance of healing in patients with erosive esophagitis, especially Los Angeles grades C and D [67]. (See "Initial management of gastroesophageal reflux disease in adults", section on 'Patients with esophagitis'.)

Switching to a PCAB is also an option in patients with refractory GERD symptoms, regardless of the background GERD phenotype; however, data to support this therapeutic approach are less robust [68-70]. (See "Initial management of gastroesophageal reflux disease in adults", section on 'Vonoprazan as alternative'.)

•Antireflux surgery – Antireflux surgery is reserved for patients who require high doses of PPIs or PCABs to heal erosive esophagitis and/or control abnormal esophageal acid exposure and symptoms. Otherwise, surgery should be carefully considered in patients who have not responded to PPI therapy [57,71]. (See "Surgical treatment of gastroesophageal reflux in adults".)

•Endoscopic procedures – Although limited data support a potential role for endoscopic procedures in managing refractory GERD, the long-term efficacy of these techniques has not been established. Several endoscopic techniques, such as transoral incisionless fundoplication (TIF) and antireflux mucosectomy, have demonstrated improvement in symptoms and reduction in PPI consumption in those with refractory GERD (partial response) [72-74]. Endoscopic techniques have a limited role in patients with persistent Los Angeles grade C or D erosive esophagitis despite optimal treatment. (See "Radiofrequency treatment for gastroesophageal reflux disease".)

●Specific patient groups

•Large hiatal hernia – Antireflux surgery with hernia repair is typically indicated in patients with significant structural disruption at the esophagogastric junction or a large hiatal hernia (>5 cm). (See "Surgical treatment of gastroesophageal reflux in adults", section on 'Gastrointestinal indications'.)

•Obesity – In patients with refractory GERD symptoms and BMI >35 kg/m², we prefer bariatric surgery, preferably Roux-en-Y gastric bypass, over antireflux surgery.

•Delayed gastric emptying – We reserve prokinetic agents, such as metoclopramide, for individuals with refractory GERD symptoms and objective evidence of delayed gastric emptying on diagnostic testing. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis", section on 'Assess gastric motility'.)

A meta-analysis of 12 randomized trials that included 2403 patients with GERD demonstrated modest reductions in symptom scores when prokinetics were added to PPI therapy in those without gastroparesis [75]. However, the combination did not increase healing of erosive esophagitis or improve esophageal motor performance. Participants treated with prokinetics were also more likely to experience adverse effects. (See "Treatment of gastroparesis", section on 'Prokinetics'.)

Normal pH testing — Individuals with refractory GERD symptoms who have normal endoscopy and impedance pH testing commonly have coexisting reflux hypersensitivity or functional heartburn. Patients whose symptoms correlate with reflux events on impedance pH testing have an overlap with reflux hypersensitivity; those without symptom correlation typically have an overlap with functional heartburn. (See 'Overlap with disorders of gut-brain interaction' above.)

●Counseling – We counsel these patients that reflux hypersensitivity and functional heartburn are disorders of gut-brain interaction that can amplify reflux-like symptoms but have a benign prognosis.

●Neuromodulators – In GERD patients with an overlap with functional heartburn or reflux hypersensitivity, we suggest a trial of a neuromodulator, such as a tricyclic antidepressant, selective serotonin reuptake inhibitor, or serotonin-norepinephrine reuptake inhibitor. We usually begin with nortriptyline 10 mg, citalopram 10 mg, or fluoxetine 10 mg and increase to the lowest effective dose based on patient tolerance and symptom response. Due to the delayed onset of action of antidepressants, patients should undergo a two- to four-week trial of therapy before increasing the dose. We usually continue treatment for 12 weeks before stopping if it is ineffective.

Neuromodulators have been shown to improve esophageal pain in patients with other functional esophageal disorders, such as functional chest pain. Limited evidence from randomized trials supports the efficacy of neuromodulators for the treatment of reflux hypersensitivity and functional heartburn [76-79]. In a trial that included 75 patients with reflux hypersensitivity on impedance pH testing, citalopram 20 mg reduced patient-reported reflux symptoms, compared with placebo (39 versus 67 percent) at six-month follow-up [77].

●Role of acid suppressive therapy – We usually continue PPI therapy in patients with refractory GERD and an overlap with reflux hypersensitivity or functional heartburn due to the history of documented GERD. In patients whose symptoms improve with a neuromodulator, it is reasonable to step down to a once-daily PPI or lower dose of a PCAB for those on this medication (eg, vonoprazan 10 mg daily).

●Baclofen for those with predominant regurgitation – In patients with refractory GERD symptoms who have predominant symptoms of regurgitation, we suggest baclofen as an adjunct to acid suppressive therapy. Baclofen is also an option for individuals with refractory GERD overlapping with reflux hypersensitivity, although the benefit is likely modest [71].

•Administration and treatment duration – We initiate baclofen at a low dose (5 to 20 mg at bedtime or 5 to 10 mg twice a day before meals). In those whose symptoms persist, we incrementally increase the dose by 5 mg every four days to a maximum dose of 20 mg three times daily. Patients who tolerate baclofen should continue it for four to eight weeks to determine its effectiveness. They should then stop the medication if symptoms do not improve.

•Side effects – Careful monitoring for central nervous system side effects is important during dose titration because baclofen crosses the blood-brain barrier. Common side effects include somnolence, confusion, dizziness, lightheadedness, drowsiness, weakness, and trembling.

•Efficacy – In a meta-analysis of nine randomized trials that included 283 patients with GERD and healthy volunteers, baclofen reduced the number and average length of reflux episodes and the incidence of transient lower esophageal sphincter relaxation [80]. However, only one of the trials evaluated baclofen as an adjunct to PPI therapy, and the study had a short duration of follow-up. (See "Non-acid reflux: Clinical manifestations, diagnosis, and management", section on 'Reflux inhibitors'.)

●Other therapies

•Psychologic interventions – We offer behavioral interventions as treatment adjuncts to individuals with esophageal hypervigilance or psychiatric comorbidities. These include hypnotherapy, cognitive behavioral therapy, mindfulness, diaphragmatic breathing, and relaxation techniques [81]. Specific psychologic interventions have been developed to address esophageal hypervigilance.

•Acupuncture – Although acupuncture may have utility as an adjunct to acid suppressive therapy in patients with refractory GERD symptoms, only limited data support its efficacy [82,83]. In a trial of 30 patients with classic heartburn refractory to once daily PPI, participants randomized to adding acupuncture to PPI therapy experienced significant improvement in regurgitation and heartburn symptoms, compared with their baseline, while those randomized to double-dose PPI did not demonstrate similar improvements [84]. Acupuncture may improve GERD symptoms by treating visceral pain.

Patients without testing — For individuals with refractory GERD symptoms who are unable or unwilling to undergo any testing, we pursue empiric treatment based on the patient's predominant symptom.

●Regurgitation – In patients with predominant regurgitation, we suggest adding baclofen. In those on PPI therapy, an additional option is to switch to a PCAB. (See 'Residual erosive esophagitis or acid reflux' above.)

●Heartburn – In patients with predominant heartburn, we generally begin by adding an H2RA at bedtime but advise intermittent use to avoid tachyphylaxis. Alternative options include adding sodium alginate at bedtime or switching PPI therapy to a PCAB (see 'Residual erosive esophagitis or acid reflux' above). We reserve neuromodulators (eg, nortriptyline, citalopram) for those whose symptoms persist despite use of a PCAB, H2RA, or sodium alginate. (See 'Normal pH testing' above.)

Abnormal esophageal manometry — Esophageal manometry can diagnose an esophageal motility disorder or rumination syndrome. Management of these individuals is discussed separately. (See "Distal esophageal spasm and hypercontractile esophagus", section on 'Management' and "Overview of the treatment of achalasia" and "Rumination syndrome", section on 'Management'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gastroesophageal reflux in adults" and "Society guideline links: Esophageal manometry and pH testing".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Acid reflux and GERD in adults (The Basics)")

●Beyond the Basics topic (see "Patient education: Gastroesophageal reflux disease in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Approximately 50 percent of patients with gastroesophageal reflux disease (GERD) have persistent symptoms despite a proton pump inhibitor (PPI) twice daily. Causes of refractory GERD symptoms include persistent reflux, coexisting functional esophageal disorders, anatomic or motor disorders of the upper gastrointestinal tract, and other diagnoses. (See 'Epidemiology' above and 'Causes of refractory GERD symptoms' above.)

●Initial assessment and alarm features – The initial assessment of individuals with refractory GERD symptoms includes asking about the timing, quality, and severity of symptoms; medication adherence; response to acid suppressive medications; and alarm features. Alarm features include:

•Evidence of gastrointestinal bleeding (hematemesis, melena, hematochezia, occult blood in stool, iron deficiency anemia)

•Anorexia

•Unexplained weight loss

•Dysphagia

•Odynophagia

•Persistent nausea/vomiting

Diagnostic evaluation and initial management – The diagnostic evaluation in patients with refractory GERD depends primarily on the presence of alarm features (algorithm 1).

•Patients with alarm features – We perform prompt upper endoscopy and pursue additional evaluation in those whose symptoms suggest underlying cancer. Patients with a negative workup are managed the same as those without alarm features (algorithm 1). (See 'Patients with alarm features' above.)

•Patients without alarm features – Initial management in patients with refractory GERD symptoms consists of reinforcing lifestyle changes and medication adherence (table 1 and table 2).

In patients taking a PPI, we reinforce the timing of medication (ie, 30 to 60 minutes before breakfast). Patients can also split the PPI dose (AM and PM). If symptoms persist despite these measures, we suggest switching to a different PPI (Grade 2C). Doubling the PPI dose is an option if switching the PPI does not relieve symptoms.

●Subsequent evaluation if symptoms persist – In all individuals whose symptoms persist despite optimizing acid suppressive therapy, we perform an upper endoscopy with possible biopsies if not previously done. If endoscopy demonstrates erosive esophagitis (Los Angeles Grade B to D), we switch to a potassium-competitive acid blocker (PCAB) or consider surgical interventions.

If endoscopy is unremarkable, we perform esophageal impedance pH testing on treatment (twice daily PPI or full-dose PCAB) and esophageal manometry. (See 'No recent prior endoscopy' above.)

●Additional measures based on esophageal impedance pH testing – In patients who undergo impedance pH testing, subsequent management is based on test results (algorithm 1). We manage patientsꞌ symptoms empirically if they cannot undergo impedance pH testing. (See 'Patients without testing' above.)

•Residual acid reflux – In patients with persistent acid reflux on esophageal impedance pH testing or when testing is unavailable and patients primarily report heartburn, we suggest adding a histamine 2 receptor antagonist at bedtime (Grade 2C). Other medical options include adding sodium alginate (eg, aluminum hydroxide-magnesium carbonate) at bedtime or switching to a PCAB. Nonmedical options include endoscopic therapy or antireflux surgery. (See 'Residual erosive esophagitis or acid reflux' above.)

•Normal pH testing – In patients with refractory GERD symptoms and a normal esophageal impedance pH study and esophageal manometry, we suggest a trial of a neuromodulator in addition to PPI treatment (Grade 2C). Neuromodulators include tricyclic antidepressants, selective serotonin reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors. (See 'Normal pH testing' above.)

In patients with refractory GERD overlapping with reflux hypersensitivity or when testing is unavailable and patients primarily report regurgitation, we suggest a trial of baclofen (Grade 2C). Antireflux surgery is offered to carefully selected patients or those with a large hiatal hernia.

We reserve the use of prokinetic agents for individuals with refractory GERD symptoms and documented evidence of delayed gastric emptying. (See 'Residual erosive esophagitis or acid reflux' above and "Treatment of gastroparesis", section on 'Prokinetics'.)